A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritis

摘要: Objective We previously observed the association of co-occurrence HLA–DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at onset rheumatoid arthritis (RA) in 182 factor (RF)–positive European American patients early-onset RA. The aim this study was to fine-map 48-kb region extended cohort 210 RF-positive early RA, seek replication RA-associated SNPs additional RA cohorts 501 Americans 298 African Americans, explore functional consequences SNPs. Methods SNP genotyping conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations rs7984870 expression plasma, peripheral blood mononuclear cells, isolated T cells were quantified enzyme-linked immunosorbent assay reverse transcription–PCR. Site-directed mutagenesis within 2-kb promoter performed drive luciferase reporter gene osteoblast stromal cell lines. Interaction DNA protein determined by electrophoretic mobility shift assay. Results A single SNP, rs7984870, consistently significantly associated earlier 3 independent seropositive (RF anti–cyclic citrullinated peptide antibody) but not seronegative patients. C risk allele conferred 2-fold higher plasma levels elevated messenger RNA activated normal increased activity after stimulation vitro via differential binding transcription SOX5. Conclusion The that upon might promote interaction between dendritic predisposing a